Effect of an Aspartame-Ethanol Mixture on Daphnia magna Cardiac Activity
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Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences
2009
Effect of an Aspartame-Ethanol Mixture on Daphnia magna
Cardiac Activity
Stephanie Schleidt1, Danielle Indelicato2, Ashley Feigenbutz1, Cierra Lewis1, and Rebecca
Kohn2
1
Neuroscience Department, Ursinus College, Collegeville, Pennsylvania, 19426, 2Biology Department, Ursinus
College, Collegeville, PA, 19426
Aspartame in conjunction with alcohol has been shown to increase the blood alcohol level in
humans faster than alcohol and sucrose (Wu et al., 2006). To determine the potential effects of
various mixtures of ethanol and aspartame on the nervous system, the heart rate of Daphnia
magna (D.magna, water flea) was measured in deionized water (control), ethanol, aspartame,
and five different mixtures of ethanol and aspartame. The heart rate was chosen as a
representative measure since it is controlled by the nervous system and the heart rate of D.
magna can easily be measured. The results were statistically evaluated by student’s t-test. A
significant increase in heart rate was observed for all mixed assays compared to both control and
ethanol, but not to aspartame. The data suggests that the aspartame and alcohol mixture have a
greater effect on D. magna heart rate than water or ethanol, but not aspartame alone. We propose
that alcohol in combination with aspartame has potentially detrimental consequences for the
nervous system.
Keywords: Daphnia magna; nervous system; aspartame; alcohol; metabolism; neuropathology;
blood alcohol level
Introduction
Stimulants and depressants, specifically been shown to cause neurological and
aspartame and alcohol, have been the focal point behavioral symptoms in certain individuals
in many scientific studies both in conjunction ranging from headaches and mood alterations to
with each other and as separate entities. The dizziness and insomnia (Bradsiock et al., 1986).
combination of aspartame and alcohol has These symptoms are thought to result from the
resulted in a marked increase in blood alcohol role each component of aspartame plays once
levels when compared to alcohol and sugar (Wu entering the body (Butchko et al., 2002).
et al., 2006). Anecdotal reports suggest that Fifty percent of aspartame is comprised
alcohol and aspartame, a component of diet of phenylalanine, which is either converted in
sodas, are popular, particularly among women, the liver to tyrosine (a non-essential amino acid)
to minimize the caloric intake of mixed or remains unchanged. In order for either
alcoholic beverages (Henkel, 1999). tyrosine or phenylalanine to cross the blood
brain barrier (BBB), binding to a large neutral
Aspartame amino acid transporter (NAAT) must occur
Aspartame, an artificial sweetener, was (Humphries et al, 2008). Since NAAT is the
approved by the U.S. Food and Drug only way in which phenylalanine, tyrosine, and
Administration in 1981 and has been used as a other amino acids can cross the BBB, a great
tabletop sweetener and in beverages, breakfast deal of competition exists for the limited binding
cereals, desserts, and chewing gum since then sites (Humphries et al., 2008). Increased
(Henkel, 1999). Aspartame consumption has aspartame intake increases the number of NAATPage 2 of 9
Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences
2009
sites occupied by phenylalanine, therefore known as acidosis (Humphries et al., 2008).
inhibiting the transportation of other essential Methanol poisoning has been shown to result in
neutral amino acids into the brain. (Yokogoshi et dizziness, headaches, and behavioral alterations,
al., 1984; Coulombe and Sharma, 1986). The which are all effects that have been reported
increase of phenylalanine in the brain has been from aspartame consumption (Thomas, 2005).
seen to cause a phenylketonuria effect, which is Several studies have shown the
a hereditary disorder characterized by the detrimental effects of aspartame metabolites on
accumulation of phenylalanine (Mehl-Madrona, the nervous system. One specific study on the
2005). This results in a decrease in the acetylcholinesterase of the frontal cortex of
dopamine and serotonin production and since suckling rats concluded that the increased
serotonin plays a critical role in behavior, concentration of metabolites in the bloodstream
control of sleep, appetite, and neuroendocrine resulted in seizures, memory loss, headaches,
function, a decrease in serotonin levels will have and cholinergic defects (Simintzi et al., 2007).
effects on these behaviors (Humphries et al., This led researchers to conclude that high
2008). dosages (toxic levels) of aspartame are
Aspartic acid, also known as aspartate, detrimental to the nervous systems of the rats,
is an excitatory neurotransmitter in the central even though the consumption of normal levels of
nervous system (CNS) and comprises 40% of aspartame showed little effect on their frontal
aspartame. Aspartic acid increases depolariza- cortex. Interestingly, aspartame itself had little
tion at the postsynaptic membrane. The effect, but the metabolites were responsible for
increased depolarization can induce the decreased enzymatic activity (Simintzi et al.,
neuroendocrine disturbances and the rapid firing 2007). Not only has aspartame been shown to
of neurons ultimately results in the failure of have an effect on enzyme activity, but it has
enzymes to function optimally (Humphries et al., been suggested to disrupt the metabolism of
2008). Unlike other amino acids in the brain, amino acids, protein structure, neuronal function,
aspartic acid is not one of the essential amino and catecholamine concentrations in the brain
acids. As a result of the excitatory effects of (Humphries et al., 2008).
aspartic acid, the concentration in the brain must
be controlled to prevent excess stimulation of Alcohol
the nerve cells (Magnuson, 2007). Heavy alcohol consumption has been
Methanol, constituting 10% of shown to cause depressive episodes, severe
aspartame, is poisonous at temperatures above anxiety, insomnia, temporary cognitive defects,
86°F and therefore becomes toxic once and peripheral neuropathy (Schuckit, 2009).
aspartame is ingested. Methanol is found Once alcohol is consumed, about 98% enters the
naturally in fruits and vegetables, but in that case bloodstream through the walls of the small
it is bound to pectin. When it is bound to pectin, intestine (Schuckit, 2009).
the body is unable to break down the molecule Alcohol, regardless of the dose,
and therefore the methanol is never released into enhances the activity in the inhibitory γ-
the bloodstream (Thomas, 2005). In aspartame, aminobutyric acid (GABA) systems throughout
methanol is not bound to pectin and is therefore the brain (Schuckit, 2009). GABA is an
considered to be in its “free” form. In this case, inhibitory neurotransmitter that binds to specific
the methanol is released to a greater degree and transmembrane receptors in the plasma
at an increased rate (Magnuson, 2007). The membrane of the pre-synaptic and post-synaptic
methanol present from the breakdown of neurons. Upon binding, ion channels open
aspartame is converted in the liver to resulting in the influx of chloride ions or the
formaldehyde, which is a known neurotoxin and efflux of potassium ions. When alcohol is
carcinogen (Humphries et al., 2008). introduced into the system, the inhibitory action
Formaldehyde is further broken down into of GABA is augmented. Since GABA is not
formic acid, which accumulates in the brain, present in one specific location in the brain, but
kidneys, spinal fluid, and other organs and can rather in several locations, the presence of
lead to excess acid in body fluids, which is alcohol inhibits several activities in the brainPage 3 of 9
Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences
2009
resulting in behavioral changes including muscle 2006). Participants in a study who consumed
relaxation and somnolence (Schuckit, 2009). “diet-alcoholic” drinks containing aspartame
Alcohol consumption also stimulates the were found to have higher blood-alcohol levels
neurons of the serotonergic system, which is when compared to those consuming alcoholic
located in the raphe nucleus at the base of the drinks containing sucrose (Wu et al, 2006). In
brain (Schuckit, 2009). This area influences addition, alcohol, like aspartame, has been found
brain functions that are related to attention, to affect heart rate. Alcohol has a depressive
emotions, and motivation (Lovinger, 1991). effect on the nervous system by first depressing
Studies have shown that individuals who the highest cerebral centers of the brain
consume large amounts of alcohol have (prefrontal cortex) then the motor and sensory
differences in brain serotonin levels in centers, the cerebellum, spinal cord and finally
comparison to non-alcoholics (Lovinger, 1991). the medulla (Karpas, 1916). The medulla is
Lovinger (1991) also showed that both short and responsible for controlling breathing, heart rate
long term exposure of alcohol has an effect on and other basic involuntary functions in the body.
the serotonin receptors that convert the signal By depressing this part of the brain, alcohol can
produced by serotonin into functional changes in also reduce heart rate.
the signal-receiving cell.Even a single exposure Since the heart rate is modulated by
to alcohol has an effect on the synaptic functions different parts of the brain, the heart rate can be
of serotonin. Upon alcohol ingestion, levels of used in order to determine the effect of
serotonin metabolites in the urine and blood aspartame and alcohol, both combined and as
increase, indicating an increase in serotonin separate entities, on the nervous system
release from the nervous system. This has been (Guyenet, 1990).
suggested to be a result of enhanced signal The small fresh water crustacean, D.
transmission at serotonergic synapses (Lovinger, magna, was used in this experiment because of
1991). Research investigating the effects of their transparent carapace, which allows for
ethanol on the nervous system has shown that increased visibility of the internal organs and
alcohol has the ability to disrupt an active makes monitoring the heart rate of the individual
fragment of the activity-dependent neuro- easier (Environmental Inquiry, 2006). It was
protective protein (ADNP) called NAPVSIPQ hypothesized that treatment with aspartame (a
(NAP) (Chen and Charness, 2008). NAP is an stimulant) alone would increase the heart rate
octapeptide that is necessary in signaling Fyn while treatment with alcohol (a depressant)
Kinase (a member of the Scr Family Kinase), would depress the heart rate. Since alcohol and
resulting in normal axonal outgrowth in cerebral aspartame have opposite effects on the nervous
granule cells, found in the brain (Chen and system, it was thought that the combination
Charness, 2008). NAP has been shown to protect would result in a heart rate comparable to the
the nervous system against a wide variety of base heart rate of D. magna. D. magna were
insults, including alcohol exposure. Therefore, treated with alcohol and aspartame alone and in
disrupting the activity of NAP and the presence different combinations to determine the effect on
of excess ethanol due to social drinking in the nervous system.
humans have resulted in neuronal migratory Materials and Methods
malfunctions, improper axonal-dendritic
connections, as well as apoptosis of glial and Daphnia magna
neuronal progenitor cells (Chen and Charness, All D. magna used in this experiment
2008). were purchased through Ward’s Natural
Science© and housed in containers containing
Alcohol and Aspartame spring water. D. magna utilized were of
In recent years, “sugar-free” alcoholic different sizes and states of maturity.
beverages have become more popular, but
consuming alcoholic beverages that contain Ethanol Solutions
aspartame in place of sucrose may result in a Preliminary tests showed that a 2.0%
greater degree of adverse effects (Wu et al, alcohol stock solution, manufactured by Ward’sPage 4 of 9
Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences
2009
Natural Science© (Rochester, New York), was twenty D. magna were used in the mixed assays.
fatal for D. magna, but 0.2% elicited a decrease For Assay # 1 n=21, for Assay # 2 n=21, for
in heart rate without fatalities. Four successive Assay # 3 n=22, for Assay 4# n=29, and for
ethanol dilutions in deionized water were then Assay # 5 n=27.
prepared: 34.32 mM (0.2%), 17.16 mM (0.1%),
8.58 mM (0.05%), and 4.29 mM (0.025%). The Table 1. Mixed assay concentrations for ethanol and
amount of alcohol ingested could not be aspartame in 50 µL.
determined since the alcohol level in the fleas
could not be measured. Forty D. magna were Assay # Ethanol (mM) Aspartame (mM)
used in the ethanol assays, n=10 for each 1 30.89 1.0
concentration. 2 24.02 3.0
3 17.16 5.0
Aspartame Solutions 4 10.30 7.0
Equal® was used as the source of 5 3.43 9.0
aspartame. Three solutions with the following
concentrations; 10.0 mM, 1.0 mM, and 0.1 mM Heart Rate Acquisition
in deionized water were prepared. It has been Each D. magna was chosen randomly
discussed that, in humans, aspartame only has and removed from a jar of fresh water with a
negative effects at levels much higher that the plastic pipette and transferred individually onto
recommended 40 – 50 mg/kg body weight/ day a concave microscope slide. Any water
(Magnuson, 2007). Thus, a high concentration of remaining on the slide was entirely absorbed
aspartame was chosen for the initial assay. The with a paper towel. Then D. magna were
solubility of aspartame is about 30 g/L at room submerged in 50.0 µL of one of the following:
temperature. Considering a molecular weight of deionized water for the base heart rate, alcohol
294.31 g/mole for aspartame, a starting solution solutions, aspartame solutions, or mixed assays.
of 10.0 mM was close to the maximum Subsequently, D. magna were allowed to
concentration at room temperature. It is difficult acclimatize to the environment for two minutes,
to judge how much of the compound was and then the heart rate was counted for one
ingested by D. magna, but based on an estimated minute. Heart rate was recorded with the use of
average body weight of 30.0 mg, the organisms a hand held, manual counter. A different D.
were exposed to 49.05 g/kg body weight (10.0 magna was used for each assay.
mM), 4.905 g/kg body weight (1.0 nM), and The base heart rate was acquired by
0.49 g/kg body weight (0.1 mM). Thirty D. transferring each D. magna into deionized water,
magna were used in the ethanol assays, n=10 for allowing it to acclimatize for two minutes, and
each concentration. recording heart rates for one minute. Statistical
analysis was performed similarly in the other
parts of the experiment. Fifty D. magna were
used for the base heart rate assay.
Mixed Assays
Five mixed assays were made from Statistical Analysis
initial concentrations of 34.32 mM (0.2%) The average heart rate and standard
ethanol and 10.0 mM aspartame. The error of the mean (SEM) were calculated for
concentration of ethanol in each successive each concentration of each part of the
mixture decreased while the aspartame experiment (ethanol, aspartame, and mixed
concentration increased (Table 1). This type of assays). Statistical significance at α = 0.05 and
varying solution was chosen to parallel alcoholic α = 0.01 was evaluated using the student’s t-test.
drinks with diet soda, since the proportion of
All calculations were performed on the
alcohol in those drinks varies inversely with the
statistical software SPSS.
amount of aspartame. Similarly, in this
experiment the volume of liquid the organism
was exposed to was limited. One-hundred andPage 5 of 9
Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences
2009
Results heart rates with increasing concentrations,
compared to base rate (Fig. 2). When compared
Base Heart Rate to the base rate the highest increase in heart rate
To compare the effects of aspartame and was observed at a concentration of 10.0 mM
alcohol on the cardiac activity of D. magna, a with a heart rate of 243 +/- 9 bpm (t (30.6) =
base heart rate (BR) of 204 +/- 7 beats per -4.09, p < .01, n=10) (Fig. 2).
minute (bpm) was established (n=50).
Heart Rate in Mixed Assay
Heart Rate in Ethanol
In order to evaluate changes in D.
magna heart rate in ethanol the fleas were
exposed to increasing ethanol concentrations
(4.29, 8.58, 17.16, and 34.32 mM). The alcohol
showed an overall depressive trend on heart rate.
However, only ethanol concentrations 17.16 and
34.32 mM showed a significant decrease with
Figure 2. D. magna heart rate change in aspartame. D.
magna heart rate was significantly increased from base
rate in 10.0 mM aspartame but not in any of the two
lower concentrations. Thus, in subsequent testing 10.0
mM of aspartame concentration was used. Bars represent
SEM; n = 10 for 10.0 mM and 0.1 mM; n = 11 for
concentration 1.0 mM; * = p < .01
Figure 1. Daphnia magna heart rate change in
To evaluate possible influences of
ethanol. Heart rate in increasing ethanol concentrations ethanol in combination with aspartame on heart
was compared to base rate. Generally, a depressant rate, a series of mixed assays were administered
trend was seen, but only concentrations 17.16 and 34.43 (Table 1). The base solutions for the mixed
mM decreased heart rate significantly. 34.32 mM was assays were 34.32 mM ethanol and 10.0 mM
used for subsequent testing. Error is SEM, n = 10 for aspartame, which were chosen because each
each concentration, n = 50 for BR; * = p < .01. caused the greatest depression or stimulation of
heart rate respectively.
total heart rates of 180 +/- 4 bpm (t (54.7) = 3.24, Both ethanol and aspartame were
p < .01, n = 10) and 133 +/- 8 bpm (t (23.32) = observed to be different from base rate, as
6.95, p < .01, n = 10) respectively (Fig. 1). For mentioned before. When compared to base rate,
further investigation, an ethanol concentration of Assays # 1 through # 5 also showed significant
34.32 mM was utilized to capitalize on the most differences with Assay #1 at 250 +/- 3 bpm (t
pronounced depressive effect of this (66.12) = -6.26, p < .01, n = 21), Assay # 2 at
concentration. 248 +/- 4 bpm (t (68.82) = -5.50, p < .01, n = 21),
Assay # 3 at 233 +/- 4 bpm (t (69.97) = -3.63, p
Heart Rate in Aspartame < .01, n = 22), Assay # 4 at 231 +/- 3 bpm (t
To assess changes of heart rate in (63.68) = -3.67, p < .01, n = 29), and Assay # 5
aspartame three different concentrations of at 234 +/- 5 bpm (t (74.98) = -3.63, p < .01, n =
aspartame were examined (10.0 mM, 1.0 mM, 27) (Fig. 3, significance denoted by *).
Increases in heart rate were found for all
and 0.1 mM). When D. magna was submerged combination assays, when compared to heart
in aspartame, the fleas tended to exhibit higher rate in ethanol alone (Assay # 1 with t ( 29) =Page 6 of 9
Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences
2009
16.38, p < .01; # 2 with t (29) = 13.68, p < .01; potentially be eliminated with further testing.
Assay # 3 with t ( 30) = 11.93, p < .01; Assay # The results obtained could be due to a novel
4 with t (37) = 15.07, p < .01, and Assay # 5 metabolic pathway involved in the combined
with t (35) = 10.838, p < .01) (Fig. 3, depicted processing of ethanol and aspartame or due to
by o). the aspartame pathway that could partially
When comparing each assay with its override the depressive effect of alcohol.
successive assay (Assay # 1 with # 2, Assay # 2 The nervous system activity of D.
with # 3, Assay # 3 with # 4, and Assay # 4 with magna, gauged by cardiac output, was greatly
# 5), only Assay # 3 was observed to be affected by the introduction of a stimulant, a
significantly different from its preceding Assay depressant, and a combination of both. D.
# 2 (t ( 41) = 2.39, p < .05) (Fig. 3, denoted by +). magna, has become an established model
Heart rate in aspartame was not different from organism because they are easily cultured and
any of Assays # 1-5 (Fig. 3). have short reproductive cycles. While the main
areas of focus on D. magna as a model organism
lie in ecology and evolution, it has been shown
Discussion that the crustacean exhibits about a 55% genetic
homology with humans, suggesting it to be
In the first experiments conducted eligible as a model for some for human
(ethanol assay), a decrease in heart rate was processes (Gilbert, 2007).
observed with increasing ethanol concentrations The experiments conducted were to
demonstrating that ethanol has a depressive understand the side effects and the mechanisms
effect on heart rate. Heart rate was considered that underlie the process of how stimulants and
representative of the actions on the nervous depressants affect nervous system activity.
system for the purpose of this experiment Previous research on stimulants has found that
because the heart rate is regulated by the they increase CNS or sympathetic nervous
nervous system in D. Magna, and therefore system activity with a spectrum of effects such
changes in heart rate were used to assess as cardiovascular stimulation and increased
changes in nervous system activity (Guyenet, energy levels (Rothman and Baumann, 2003). In
1990). the presence of stimulants, synaptic levels of
The second part of the experiment, in monoamine neurotransmitters are elevated in
which D. magna were introduced to various neurons, specifically dopamine, serotonin, and
concentrations of aspartame, resulted in an norepinepherin (Sofuoglu and Sewell, 2008).
increase in heart rate as the concentration of Neurotransmitter concentrations increase as a
aspartame solutions increased, confirming the result of blocking transporter–mediated reuptake
stimulant effect of aspartame. inhibitors from the synapse (Rothman and
In the final part of the experiment, Baumann, 2003). Excess levels of serotonin
mixed assays of aspartame and ethanol were have been associated with cardiac and
used to determine the combined effects of a pulmonary disease, and stimulants such as
stimulant and a depressant. The results of the amphetamine analogs act as substrates for the
mixed assay (Fig. 3) showed a marked increase serotonin transporters, which release serotonin
of D. magna heart rate with even a minimal from platelets, in turn elevating plasma blood
addition of aspartame to ethanol (Assay # 1). levels of the neurotransmitter (Zolkowska et al.,
These findings suggest that the ingestion of 2006). Plasma serotonin stimulates mitogenic
aspartame has a greater impact on heart rate than activity from cardiovascular cells (Zolkowska et
alcohol. There was no systematic difference al., 2006).
among Assays #1 – 5 or when comparing the Depressants also affect CNS activity
assays with aspartame alone. This may indicate through different mechanisms. Ethanol, a
that any amount of aspartame in combination depressant, enhances GABAergic synaptic
with alcohol has a significant influence on D. inhibition by means of allosteric potentiation of
magna metabolism and heart rate. The postsynaptic GABA receptors (Ariwodola and
difference between Assays # 2 and # 3 could Weiner, 2004). This mechanism plays a vitalPage 7 of 9
Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences
2009
role in the effects of ethanol, most notably on provides a basis for understanding the possible
cognition. GABA receptors are responsible for side effects of excessive consumption of
mediating fast synaptic inhibition. Hippocampal aspartame in conjunction with alcohol. Human
GABA activity is potentiated by ethanol when studies have shown that aspartame can cause
there is a blockade of GABA B receptors migraines, seizures, depression and anxiety
(Ariwodola and Weiner, 2004). Ethanol was (Bradsiock et al., 1986). Alcohol has been linked
also found to increase GABAergic transmission to depression, anxiety and cognitive deficits
into the ventral-tegmental area dopaminergic (Schuckit, 2009). Thus temporary or long-term
neurons, in which GABA inhibitory post nervous system alterations by alcohol and
synaptic currents are enhanced (Theile et al., aspartame may cause serious health risks that
2008). The increase of overall GABA in the have not yet been identified but could become
CNS produces a decrease in cardiovascular manifest with increasing consumption of
activity (Segura and Haywood, 1991). aspartame in the future.
Considering the large increase in D.
magna heart rate in all five mixed assays, further
investigation appears to be warranted aimed at Acknowledgements
identifying similar effects in larger organisms
like mice, and eventually in humans. We thank Ursinus College for funding our
Examination of larger animals would allow research.
controlling the amount of ingested alcohol and
aspartame. Memory or behavior tasks could then
be used to evaluate other effects of the mixture
on nervous system functions. Furthermore,
Corresponding Author
neurotransmitter levels in the brain of these
Cierra Jené Lewis
animals could be measured. The results could
Ursinus College
shed light on the pathways involved in the
rkohn@ursinus.edu
metabolism of alcohol in conjunction with
601 E Main Street
aspartame. We also suggest investigating the
Collegeville, PA 19426
effect of aspartame doses that come closer to the
maximum recommended amount of 40 – 50
mg/kg body weight/day.
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School of Public Health College aspartame and glucose administration on
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Am J Clin Nutr 40:1-7.You can also read
